US8541620B2 - Method for selectively crystallizing a Z isomer of iopromide - Google Patents

Method for selectively crystallizing a Z isomer of iopromide Download PDF

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Publication number
US8541620B2
US8541620B2 US13/132,791 US200913132791A US8541620B2 US 8541620 B2 US8541620 B2 US 8541620B2 US 200913132791 A US200913132791 A US 200913132791A US 8541620 B2 US8541620 B2 US 8541620B2
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iopromide
isomer
crude
concentrate
crystal
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US20110245347A1 (en
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Soo-Jin Choi
Byung-Goo Lee
Han-Kuk Lee
Young-Mook Lim
Wol-Young Kim
Joon-Hwan Lee
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Daewoong Pharmaceutical Co Ltd
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Daewoong Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/22—Separation; Purification; Stabilisation; Use of additives
    • C07C231/24—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/67—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/68—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/69—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom of an acyclic saturated carbon skeleton

Definitions

  • the present invention relates to a method for selectively crystallizing a Z form isomer of iopromide from a crude crystal of iopromide comprising a mixture of E and Z iopromide isomers, and a composition comprising the Z iopromide isomer prepared by said method.
  • Iopromide 5-methoxyacetylamino-2,4,6-triiodo-isophthalic acid-[(2,3-dihydroxy-N-methyl-propyl)-(2,3-dihydroxypropyl)]-diamide of Formula (I), is an iodine-containing X-ray contrast agent, and it has 3 bulky iodine atoms on the 2, 4, and 6 positions of the phenyl group, which sterically hinder the free rotation of the dihydroxypropyl-N-methylamino group, so that two atropisomer occur (M. Oki, Topics in Stereochemistry , volume 14, 1983, pp. 1 ⁇ 81; and H. Staab, et al., Tetrahedron Letters , No. 38, 1966, pp. 4593 ⁇ 4598).
  • iopromide is composed of a mixture of four isomers, and E1, E2, Z1 and Z2.
  • the substituted nitrogen atom lies above the plane of the benzene ring of iopromide, while in the other, it lies below the plane of the benzene ring.
  • the E and Z forms can be distinguished by the arrangement of the substituents around C—N bond of the dihydroxy-N-methyl-proyl amide group.
  • R is a phenyl group of iopromide.
  • isomers have different physical properties and the relative amount of a singe isomer as well as the relative contents of the isomers is regulated in a pharmaceutical formulation.
  • a pharmaceutical raw material must contain 40 to 50% of form 1 isomer and 49 to 60% of form 2 isomer, and a medicinal product must contain 8.0 to 12.0% of E1 isomer, 9.0 to 14.0% E2 isomer, 32.0 to 40.0% of Z1 isomer, and 38.0 to 46.0% of Z2 isomer.
  • U.S. Pat. No. 4,364,921 discloses a method for preparing iopromide, but, it does not employ a final crystallization step.
  • European Patent EP 1,025,067 and English Patent GB 2,280,436 disclose a method for washing and crystallizing iopamidol and iodixanol, they do not teach any crystallization procedure for iopromide or iopromide isomers.
  • An injection formulation of iopromide can be prepared by dissolving a pharmaceutical raw material in water, adding pharmaceutically acceptable excipients to the solution, and sterilizing it, but, when a conventional iopromide raw material containing E and Z isomers is used to formulate a pharmaceutical product, the relative contents of the isomers in the product often do not meet the regulation.
  • the present inventors have found that a method for selectively resolving and crystallizing Z isomer of iopromide from crystalline iopromide or an iopromide concentrate containing E and Z isomers.
  • a method for selectively crystallizing Z isomer of iopromide comprising a) dissolving a crude iopromide or a concentrate thereof containing E and Z isomers in an alcohol; and b) heating the resulting alcohol solution to selectively obtain crystalline Z isomer of iopromide.
  • a method for preparing a composition comprising Z isomer of iopromide comprising i) selectively crystallizing the Z isomer of iopromide from a crude crystal containing a mixture of E and Z isomers of iopromide or a concentrate thereof to obtain crystalline Z isomer of iopromide; and ii) dissolving the crystalline Z isomer of iopromide, together with a pharmaceutically acceptable excipient.
  • FIG. 1 a liquid chromatography scan of the inventive iopromide crystal containing the Z isomer obtained in Example 1;
  • FIG. 2 a liquid chromatography scan of the crude iopromide crystal containing E and Z isomers.
  • a method for selectively crystallizing Z isomer of iopromide comprising a) dissolving a crude iopromide containing a mixture of E and Z isomers or a concentrate thereof in an alcohol; and b) heating the alcohol solution to selectively obtain crystalline Z isomer of iopromide.
  • crude iopromide may be prepared by the method disclosed in U.S. Pat. No. 4,364,921:
  • the crude iopromide or the concentrate thereof may contain 1:0.5 to 1:10 of E isomer:Z isomer, and 0 to 15 wt % of moisture.
  • the volume (ml) of alcohol to be used for dissolving the crude crystal or the concentrate thereof is suitably from 0.1 to 10 times, preferably 1 to 3 times the weight (g) of the crude iopromide crystal or the concentrate thereof.
  • the preferred alcohol as used herein is a C 1-10 straight or branched aliphatic alcohol, preferably, methanol, ethanol, isopropanol, n-butanol, sec-butanol, pentanol, octanol, decanol or a mixture thereof.
  • heat treatment may be accomplished by various methods known in the art, preferably by heat refluxing.
  • the Z isomer may be selectively crystallized by heat refluxing for 1 to 48 hours, while keeping the vessel's external temperature at 50 to 200° C., preferably, 80 to 180° C., more preferably, 100 to 150° C., under normal atmospheric pressure.
  • the heat refluxing time can be modulated depending on an experimental scale, i.e., mass of the crude iopromide, and the above time range are intended to illustrate the present invention without limiting its scope.
  • the Z isomer content of the iopromide crystal obtained by the above method is preferably 85 to 100%, or the iopromide crystal may consist of 100% of Z form isomer or contain 5% or less of E form isomer.
  • the refluxing time can be shortened, and, therefore, a the amount of degradation products due to exposure to high temperature for a long time can be reduced.
  • a method for preparing a composition comprising a Z isomer of iopromide comprising i) selectively crystallizing Z isomer of iopromide from crude iopromide comprising a mixture of E and Z isomers of iopromide or a concentrate thereof to obtain crystalline Z isomer of iopromide; and ii) dissolving the crystalline Z isomer of iopromide, together with a pharmaceutically acceptable excipient.
  • the crystallizing step i) in the above composition preparation method is characterized in comprising 1) dissolving crude iopromide or a concentrate thereof containing E and Z isomers in an alcohol; and 2) heating the resulting alcohol solution to obtain crystalline Z isomer of iopromide, and details of the preparation method are the same as those defined as the above crystallizing method for the Z isomer of iopromide.
  • a pH adjusting agent such as NaOH, and a stabilizing agent such as calcium disodium edetate may be used in the preparation method for a Z isomer-containing composition (see U.S. Pat. No. 4,634,921), and the aqueous solvent as used herein may be water.
  • composition comprising the Z isomer of iopromide prepared by the above method may be sterilized and formulated in form of an injection formulation, and colorless and transparent liquid formulation is preferred.
  • a pharmaceutical raw material which renders the ratios of E1, E2, Z1, and Z2 isomers to be satisfied with the standards suitable for a pharmaceutical formulation such as those described in the USP.
  • a ratio of form 1 isomer:form 2 isomer can be regarded as a ratio Z1 isomer:Z2 isomer, since the ratio of form 1 isomer:form 2 isomer generally refers to (E1+Z1):(E2+Z2), and the relative amounts of E1 to Z1 and E2 and Z2 are not regulated.
  • when adjusting the relative amounts of iopromide isomers in the raw pharmaceutical material based on Z1 and Z2 will be much easier to satisfy said standard with reproducibility.
  • the isomer contents of the obtained crystal were determined by liquid chromatography using 4.6 mm ⁇ 25 cm column (5 ⁇ m L1 packing) according to the method described in the United States Phamacopoeia (USP), and the results in FIG. 1 showed that the crystal was composed of 46.4% Z1 and 53.6% Z2 (Z isomer content: 100%).
  • the isomer contents of the obtained crystal 46.8% Z1, 53.2% Z2 (Z isomer content: 100%).
  • the isomer contents of the obtained crystal 45.5% Z1, 54.5% Z2 (Z isomer content: 100%).
  • the isomer contents of the obtained crystal 47.6% Z1, 52.4% Z2 (Z isomer content: 100%).
  • the isomer contents of the obtained crystal 48.3% Z1, 51.7% Z2 (Z isomer contents: 100%).
  • the iopromide crystal prepared by the method according to the present invention satisfied the standards described in the USP and ICH guideline, and the method according to the present invention has superior effects over the conventional methods in terms of shortening the refluxing time and reducing the amount of degradation products.
  • Iopromide crystal containing only Z isomer prepared in Example 1 (Z1 isomer 46.4% and Z2 isomer 53.6%) was dissolved in 0.01 g of calcium edetate and 100 ml of secondary distilled water, and then, pH of the solution was adjusted with 0.1N NaOH to 7.2. The solution was poured into a container and sterilized for 20 minutes at 120° C. to prepare a pharmaceutical formulation. As shown in Table 2, the relative amounts of the iopromide isomers in the formulation satisfied the standards described in the USP.
  • a pharmaceutical formulation was prepared with 62.34 g of iopromide crystal (E1 isomer 8.76%, E2 isomer 10.60%, Z1 isomer 39.68% and Z2 isomer 40.97%) in the same manner as in the above Test Example 1. Then the ratios of iopromide isomers in the formation were analyzed. As shown in Table 2, the relative amounts of the iopromide isomers in the formulation do not satisfied the standards described in the USP.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
US13/132,791 2008-12-05 2009-10-21 Method for selectively crystallizing a Z isomer of iopromide Expired - Fee Related US8541620B2 (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
KR10-2008-0123138 2008-12-05
KR20080123138 2008-12-05
KR10-2009-0085014 2009-09-09
KR1020090085014A KR100976097B1 (ko) 2008-12-05 2009-09-09 이오프로마이드의 ｚ 이성체를 선택적으로 결정화하는 방법
PCT/KR2009/005827 WO2010064785A2 (fr) 2008-12-05 2009-10-12 Procédé permettant la cristallisation sélective d'un isomère z d'iopromide

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US20110245347A1 US20110245347A1 (en) 2011-10-06
US8541620B2 true US8541620B2 (en) 2013-09-24

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US (1) US8541620B2 (fr)
EP (1) EP2370396B1 (fr)
JP (1) JP5411287B2 (fr)
KR (1) KR100976097B1 (fr)
CN (1) CN102239135B (fr)
BR (1) BRPI0921244A2 (fr)
CA (1) CA2744800C (fr)
MX (1) MX2011005589A (fr)
RU (1) RU2481325C2 (fr)
WO (1) WO2010064785A2 (fr)

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KR100976097B1 (ko) * 2008-12-05 2010-08-16 주식회사 대웅제약 이오프로마이드의 ｚ 이성체를 선택적으로 결정화하는 방법
KR102174436B1 (ko) * 2017-08-17 2020-11-04 주식회사 엘지화학 불용성 안료 화합물의 정성분석방법
CN116106431A (zh) * 2021-11-09 2023-05-12 北京北陆药业股份有限公司 利用高效液相色谱法分离碘普罗胺及相关杂质的分离及定量分析方法

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2280436A (en) 1993-07-30 1995-02-01 Zambon Spa Process for crystallization of iopamidol
WO1999018054A1 (fr) 1997-10-02 1999-04-15 Nycomed Imaging As Procede de cristallisation de composes steriquement encombres
WO2007013816A1 (fr) 2005-07-29 2007-02-01 Ge Healthcare As Procede de cristallisation continue de derives phenyliques iodes
WO2007013815A1 (fr) 2005-07-29 2007-02-01 Ge Healthcare As Procede de cristallisation continue de derives de phenyle iodes
WO2007065534A1 (fr) * 2005-12-05 2007-06-14 Bayer Schering Pharma Aktiengesellschaft Procede de recuperation d'iopromide a usage pharmaceutique a partir d'eaux meres
US20070265470A1 (en) 2005-12-08 2007-11-15 Hartmut Kagerer Process for recovery of iopromide, suitable for pharmaceutical purposes, from mother liquors
WO2009134030A1 (fr) 2008-04-30 2009-11-05 Lg Life Sciences Ltd. Nouveau procédé de préparation de l’iopromide

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2909439A1 (de) * 1979-03-08 1980-09-18 Schering Ag Neue nichtionische roentgenkontrastmittel
DK2365963T3 (en) * 2008-11-18 2017-10-09 Bracco Imaging Spa PROCEDURE FOR THE PREPARATION OF IODATED CONTRACTOR
KR100976097B1 (ko) * 2008-12-05 2010-08-16 주식회사 대웅제약 이오프로마이드의 ｚ 이성체를 선택적으로 결정화하는 방법

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2280436A (en) 1993-07-30 1995-02-01 Zambon Spa Process for crystallization of iopamidol
WO1999018054A1 (fr) 1997-10-02 1999-04-15 Nycomed Imaging As Procede de cristallisation de composes steriquement encombres
WO2007013816A1 (fr) 2005-07-29 2007-02-01 Ge Healthcare As Procede de cristallisation continue de derives phenyliques iodes
WO2007013815A1 (fr) 2005-07-29 2007-02-01 Ge Healthcare As Procede de cristallisation continue de derives de phenyle iodes
WO2007065534A1 (fr) * 2005-12-05 2007-06-14 Bayer Schering Pharma Aktiengesellschaft Procede de recuperation d'iopromide a usage pharmaceutique a partir d'eaux meres
US20070265470A1 (en) 2005-12-08 2007-11-15 Hartmut Kagerer Process for recovery of iopromide, suitable for pharmaceutical purposes, from mother liquors
WO2009134030A1 (fr) 2008-04-30 2009-11-05 Lg Life Sciences Ltd. Nouveau procédé de préparation de l’iopromide
JP2011518878A (ja) 2008-04-30 2011-06-30 エルジー・ライフ・サイエンシーズ・リミテッド イオプロミドの新規な製造方法

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
European Patent Office, Supplementary European Search Report issued in corresponding EP Application No. 09 83 0523, dated Mar. 13, 2012.
Japanese Patent Office, Japanese Office Action issued in corresponding JP Application No. 2011-539442, dated Mar. 19, 2013.
WIPO IB, International Search Report for PCT/KR2009/005827 dated May 2010.

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Publication number Publication date
JP2012510510A (ja) 2012-05-10
EP2370396B1 (fr) 2019-02-20
RU2481325C2 (ru) 2013-05-10
CN102239135A (zh) 2011-11-09
KR100976097B1 (ko) 2010-08-16
EP2370396A4 (fr) 2012-04-25
CA2744800A1 (fr) 2010-06-10
US20110245347A1 (en) 2011-10-06
KR20100065064A (ko) 2010-06-15
EP2370396A2 (fr) 2011-10-05
CA2744800C (fr) 2014-05-06
CN102239135B (zh) 2014-02-12
JP5411287B2 (ja) 2014-02-12
BRPI0921244A2 (pt) 2018-06-26
WO2010064785A3 (fr) 2010-07-22
RU2011127392A (ru) 2013-01-10
WO2010064785A2 (fr) 2010-06-10
MX2011005589A (es) 2011-07-20

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